Obesity is a major public health problem, with millions of Americans suffering from weight-related health complications, including Type 2 diabetes, coronary heart disease, hypertension, and osteoarthritis. Behavioral weight loss intervention has emerged as a key strategy in combating obesity and the associated health consequences. However, individuals differ in their degree of success in these programs and genetic factors are known to play a role. In this application, we propose to identify specific genes that predict individual differences in weight loss in response to behavioral intervention to help identify individuals who struggle with weight loss despite behavioral efforts. Specifically, we will determine whether obesity genes interact with lifestyle intervention in predicting weight loss at year 1 of the Look AHEAD trial (U01DK056992), an NIH-funded, multi-center randomized controlled trial with the primary goal of determining whether weight loss achieved through an intensive lifestyle intervention can reduce cardiovascular morbidity and mortality among persons with type 2 diabetes. At year 1, participants assigned to Intensive Lifestyle Intervention (ILI), focusing on changes in diet and physical activity, lost an average of 8.6% of their weight (N= 2,496;97.1% follow-up) relative to losses of 0.7% among individuals assigned to the Diabetes Support and Education (DSE) group (N= 2,463, 95.7% follow-up), who received diabetes support and education groups alone. Consent for genetic analyses was provided by 3,759 participants. Genotype data from the IBC chip, including over 4,000 markers within genes previously associated with obesity, will allow us to test our central hypothesis that genes that predispose to obesity interact with lifestyle treatment to influence weight loss following intensive lifestyle intervention. We conduct these aims with the explicit goal of bringing together a team with expertise in behavioral research, genetic epidemiology and molecular biology to create transdisciplinary researchers who are able to bridge across the disciplines and identify key gene x behavior interactions in the context of the Look AHEAD trial. PUBLIC HEALTH RELEVANCE: The interplay of genetic and behavioral factors is critical to understanding obesity and behavioral weight loss intervention has emerged as a key strategy in combating obesity. In this application, we propose to identify specific genes that predict individual differences in weight loss in response to behavioral intervention to help identify individuals that struggle with weight loss despite behavioral efforts.